💊Medicinal Chemistry Unit 8 – Pharmaceutical Formulation & Delivery

Key Concepts

• Pharmaceutical formulation involves designing and developing a drug product that delivers the active pharmaceutical ingredient (API) effectively and safely
• Bioavailability refers to the extent and rate at which the API reaches the systemic circulation and becomes available at the site of action
• Drug delivery systems are engineered technologies for the targeted delivery and controlled release of therapeutic agents
• Pharmacokinetics studies the absorption, distribution, metabolism, and excretion (ADME) of drugs in the body
• Excipients are inactive substances used as carriers or to enhance the stability, bioavailability, or palatability of a drug
• Quality control ensures that drug products meet the required standards of identity, strength, quality, and purity
• Emerging technologies, such as nanotechnology and 3D printing, are being explored to develop novel drug formulations and delivery systems

Types of Drug Formulations

• Solid oral dosage forms include tablets, capsules, powders, and granules
  • Tablets are compressed powders or granules that may be coated or uncoated (immediate-release, extended-release, or enteric-coated)
  • Capsules are solid dosage forms in which the drug is enclosed within a hard or soft soluble container or shell (gelatin or HPMC)
• Liquid dosage forms include solutions, suspensions, emulsions, and syrups
  • Solutions are homogeneous mixtures of one or more solutes dissolved in a solvent (oral, topical, or parenteral)
  • Suspensions are heterogeneous mixtures of insoluble particles dispersed in a liquid medium (oral or topical)
• Semisolid dosage forms include ointments, creams, gels, and pastes
• Parenteral dosage forms are sterile preparations intended for administration by injection (intravenous, intramuscular, or subcutaneous)
• Novel drug delivery systems include liposomes, nanoparticles, and transdermal patches

Drug Delivery Systems

• Oral drug delivery is the most common and convenient route of administration
  • Modified-release systems control the rate or site of drug release (extended-release, delayed-release, or targeted-release)
  • Orodispersible tablets (ODTs) rapidly disintegrate in the mouth without the need for water
• Parenteral drug delivery involves the administration of drugs directly into the body via injection
  • Intravenous (IV) injection delivers the drug directly into the bloodstream for rapid onset of action
  • Intramuscular (IM) and subcutaneous (SC) injections deposit the drug into the muscle or beneath the skin for slower absorption
• Transdermal drug delivery uses patches or gels to deliver drugs through the skin
  • Suitable for drugs with low molecular weight, high lipophilicity, and low dose
• Pulmonary drug delivery involves the inhalation of drugs into the lungs (metered-dose inhalers, dry powder inhalers, or nebulizers)
• Targeted drug delivery systems aim to deliver drugs specifically to the site of action, minimizing systemic exposure (antibody-drug conjugates, nanoparticles, or liposomes)

Pharmacokinetics & Bioavailability

• Absorption is the process by which a drug moves from the site of administration into the bloodstream
  • Factors affecting absorption include the route of administration, drug formulation, and physicochemical properties of the drug (solubility, permeability, and stability)
• Distribution is the process by which a drug moves from the bloodstream into various tissues and organs
  • Plasma protein binding, tissue affinity, and blood flow influence drug distribution
• Metabolism is the biochemical modification of drugs by enzymes, primarily in the liver
  • Cytochrome P450 (CYP) enzymes play a crucial role in drug metabolism
• Excretion is the process by which drugs and their metabolites are eliminated from the body (renal, biliary, or pulmonary)
• Bioavailability is the fraction of an administered dose that reaches the systemic circulation unchanged
  • Factors affecting bioavailability include first-pass metabolism, drug solubility, and permeability
  • Absolute bioavailability compares the bioavailability of a drug given by any route to that of an intravenous dose
  • Relative bioavailability compares the bioavailability of different formulations or routes of administration

Excipients & Additives

• Diluents are inert substances used to increase the bulk of a formulation (lactose, microcrystalline cellulose, or starch)
• Binders help to hold the ingredients in a tablet together (polyvinylpyrrolidone, starch, or gelatin)
• Disintegrants promote the breakup of a tablet in the gastrointestinal tract (croscarmellose sodium, sodium starch glycolate, or crospovidone)
• Lubricants reduce friction during tablet compression and ejection (magnesium stearate, stearic acid, or talc)
• Glidants improve the flow properties of granules or powders (colloidal silicon dioxide or talc)
• Preservatives prevent microbial growth in liquid and semisolid formulations (parabens, benzalkonium chloride, or phenol)
• Sweeteners, flavors, and colors enhance the palatability and appearance of oral formulations

Formulation Techniques

• Granulation is the process of forming larger particles from smaller ones to improve flow and compressibility
  • Wet granulation involves the addition of a binder solution to powders, followed by drying and milling
  • Dry granulation involves the compaction of powders into slugs or ribbons, followed by milling
• Direct compression is the process of compressing a powder blend directly into tablets without prior granulation
  • Requires the use of directly compressible excipients with good flow and compressibility properties
• Milling is the process of reducing the particle size of drugs or excipients
  • Ball milling, jet milling, and high-pressure homogenization are common milling techniques
• Lyophilization (freeze-drying) is the process of removing water from a frozen product by sublimation under vacuum
  • Used to improve the stability of heat-sensitive or unstable drugs
• Spray drying is the process of converting a liquid feed into a dry powder by spraying it into a hot drying medium
  • Used to produce fine, homogeneous powders with controlled particle size and shape

Quality Control & Stability

• In-process controls are tests performed during the manufacturing process to ensure product quality (weight variation, hardness, or friability)
• Finished product testing ensures that the final product meets the required specifications (assay, dissolution, or impurities)
• Stability testing evaluates the ability of a drug product to maintain its quality attributes over time under the influence of environmental factors (temperature, humidity, or light)
  • Accelerated stability testing is conducted under exaggerated storage conditions to predict the long-term stability of a drug product
  • Real-time stability testing is conducted under recommended storage conditions to establish the shelf life of a drug product
• Packaging plays a crucial role in maintaining the quality and stability of drug products
  • Primary packaging is in direct contact with the drug product (blister packs, vials, or bottles)
  • Secondary packaging provides additional protection and labeling (cartons or boxes)

Emerging Technologies

• Nanotechnology involves the manipulation of matter at the nanoscale (1-100 nm) to develop novel drug delivery systems
  • Nanoparticles, liposomes, and dendrimers are examples of nanoscale drug delivery systems
  • Nanoformulations can improve drug solubility, stability, and targeted delivery
• 3D printing (additive manufacturing) is the process of creating objects by depositing materials layer by layer based on a digital model
  • Used to produce personalized dosage forms, implants, and drug delivery devices
  • Enables the fabrication of complex geometries and multi-drug combinations
• Microfluidics involves the manipulation of fluids at the microscale (1-1000 μm) to develop novel drug delivery systems
  • Microfluidic devices can be used for the continuous manufacturing of nanoparticles, liposomes, and emulsions
  • Offers precise control over particle size, composition, and drug loading
• Artificial intelligence (AI) and machine learning (ML) are being explored to optimize drug formulation and delivery
  • AI/ML can be used to predict drug solubility, stability, and bioavailability
  • Enables the design of novel excipients and drug delivery systems